Abstract Body: Introduction: Global rise in Alzheimer’s disease (AD) and dementia is linked to an aging population. Impaired proteostasis drives the progressive cognitive decline and neuronal/vascular dysfunction in AD. While neuronal Amyloid β and tau aggregation are hallmarks of AD, emerging evidence suggests that platelets may play a role in AD progression. However, the precise mechanisms by which platelet function influences AD pathogenesis remain unclear.
Hypothesis: Protein aggregate accumulation within platelets can modulate platelet activation, exacerbating the AD pathogenesis and severity.
Methods: In collaboration with Yale Alzheimer’s Disease Research Unit, blood samples from AD patients (n=14) and cognitively normal (CN) controls (n=12) were analyzed. Platelets were isolated to assess activation and apoptosis. Intraplatelet protein aggregates were quantified, isolated and characterized for composition, results validated by protein and gene expression studies. The findings were corelated with cognitive function and genetic studies. Longitudinal mouse studies (n=4; both sexes) examined the age-related changes in platelet dysfunction and protein aggregation from 2 to 9 months.
Results: Platelets from AD patients displayed significant hyperactivation and elevated inflammatory markers (TNF-α, IL-6, MCP-1). TEM confirmed the accumulation of misfolded protein aggregates in the AD platelets. The isolated protein aggregate fractions were found to be primarily rich in Aβ40, Aβ42, and phosphorylated tau proteins. AD platelets exhibited pronounced activation of Unfolded Protein Response (UPR), evident by increased GRP78 (p<0.001), and elevated PERK and IRE1α signaling. Cognitive function as assessed by MoCA and MMSE, correlated significantly (p<0.001) with platelet activation markers, intraplatelet protein aggregates, Aβ42 and pTau levels. Additionally, these intraplatelet changes differed between ApoE ε4 carriers and non-carriers (p<0.01). Longitudinal murine studies demonstrated protein aggregate accumulation with age.
Conclusions: Our findings highlight that protein aggregates and UPR activation are linked to platelet hyperactivation in AD patients. These intraplatelet changes correlate with cognitive decline severity and genetic risk factors. Regulation of platelet activation by the intracellular accumulation of aggregated proteins, likely contributes to the pathogenesis of AD and could serve as a peripheral biomarker for AD severity.